Multifaceted analysis of molecular pathogenesis of human lung cancers

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In this research project, multi faceted analyses were conducted in order to better understand the molecular pathogenesis of human lung cancers. Consequently, we have successfully obtained the following results.(1) Expression profiling analysis of lung cancer specimens using the microarray technology revealed the presence of considerable heterogeneity and also allowed us to construct a highly accurate model for predicting 5-yr survival after potentially curative resection. Expression profiling at the protein level has also initiated during this period, which will be rigorously investigated in the next term of this research project.(2) By comparing expression profiles of a highly metastatic and its parental human lung cancer cell lines established in our laboratory, various molecules related to inflammation and some other biological responses such as angiogenesis and proteasome-dependent degradation were suggested to be involved in the process of metastasis. Further, we also isolated novel genes related to metastasis including CLCP1 and LNMO1 and characterized their roles in metastasis.(3) We found the presence of persistent chromosomal instability in lung cancers and an indirect role of p53 in activation in the acquisition of chromosomal instability phenotype. We also found a homozygous deletion of 14・3・3ε at 17p13.3,a site of frequent alleic losses in lung cancers. This finding led us to identify that 14-3-3ε may play a role in G2 check point response in lung cancers. In addition, we found requently impaired decatenation G2 checkpoint in lung cancers as well as frequent epigenetic silencing of CHFR, a gene implicated in the prophase checkpoint.